1. Field of the Invention
The present invention relates to a process for the preparation of a stable multiple emulsion of the water/oil/water (WOW) type, where the external phase and also the internal aqueous phase can comprise a pharmaceutical active ingredient, and whose oil-containing phase comprises a nonionic surfactant which acts as emulsifier. This multiple emulsion is prepared by introducing the aqueous phase into the oil phase through a porous membrane and then cooling the water-in-oil (W/O) emulsion to form the abovementioned W/O/W double emulsion, which is used in particular for veterinary medicinal purposes.
2. Description of Related Art
Multiple emulsions are emulsions of emulsions which can primarily be present in two types, namely W/O/W emulsions and O/W/O emulsions. These systems are of great interest in many areas of application. They permit firstly protection of the active substances in the innermost phase, and secondly the incorporation of two active substances which react with one another into two phases of the same formulation. Furthermore, prolonged effectiveness of the active ingredients in the innermost phase can be observed following administration to organisms.
Nowadays, however, there are only a few multiple emulsions in medicine and cosmetics since their formulation and their stability still present a problem and the phenomena of emulsification have still not been completely explained. The principles are given in “Multiple W/O/W emulsions, theoretical study” Terrise, I.; M. Seiller, et al. (1992). Congr. Int. Technol. Pharm., 6th 4: 328-35.
In veterinary medicine, vaccines are required to immunize against one or more pathogens in which the active ingredient is present in the vaccine in as finely distributed a form as possible and spreads within the animal in particular over a prolonged period.
Multiple emulsions represent an interesting emulsions system for use in the vaccine formulation. They are emulsions which, in the innermost phase, comprise relatively small drops of a liquid which corresponds to the continuous outermost phase. One way of formulating such a vaccine is the multiple W/O/W emulsion. Here, the active ingredient is found, for example, in the form of an insoluble protein of a certain particle size in the aqueous innermost phase. As a result of the additional oil phase, uptake into the body is delayed, and thus the effectiveness is prolonged. Furthermore, the oil acts in some instances as an adjuvant, i.e. it can boost the antigenic effect of the vaccine.
Formulation in the form of multiple emulsions is also known from the field of cosmetics. Laid-Open Specification DE 196 30 176 A1 describes the composition of the ingredients, and the preparation of such double emulsions with the help of phase inversion.
The patent specification U.S. Pat No. 6,251,407 B1 describes a composition of oil, emulsifier, aqueous phase and pharmaceutical active ingredient which can be used for preparing a vaccine. In this, the individual constituents can be described in more detail as follows: the oil used is a so-called self-emulsifying oil which consists of polyglycolized glycerides. The aqueous phase comprises an active ingredient which is an antigen.
This double emulsion according to EP-A-489 181 or EP-A-481 982 is prepared by the “stirring” of the aqueous active ingredient-containing phase into an oily phase, and subsequent phase inversion to form a double emulsion by temperature gradients and subsequent homogenization by stirring.
The disadvantage of the W/O/W emulsion which is produced here as in the case given above is the inhomogeneous broad droplet distribution and the poor reproducibility of the droplet distribution in the finished emulsion with different stirred-tank reactor geometries. Furthermore, this process is only possible in discontinuous operation.
Furthermore, processes for producing multiple emulsions with membranes are already known. The literature source Joscelyne, S. M. and G. Tragardh (2000), “Membrane emulsification—a literature review”. J. Membr. Sci 169 (1): 107-117 describes this in detail. Here, an aqueous phase, for example, is introduced into one of the phases via a membrane. The droplet size corresponds to 2 to 10 times the pore diameter of the membrane. Limitations arise from the limiting of the particle size by the radius of the membrane pore. However, it has been found that the diameter of the membrane pore has a detrimental effect on the incorporation of an active ingredient into the emulsion if the active ingredient particle is too large.
The patent application EP 564 738 A1 a membrane process for the preparation of emulsions in which a first emulsion is effected by membrane emulsification, generation of the double emulsion is effected by stirring, or both are effected by membrane emulsification. The process serves to prepare in steps a low-fat spread in the form of a double emulsion which is characterized by economizing on stabilizers and gel formers. The final emulsion drops therein have an average diameter of from 10 to 16 μm.
All of the specified processes are only appropriate for one field of application and cannot therefore be simply transferred to further fields of use.